Benzopiperidinoalkylimides



United States Patent 3,015,662 BENZOPIPERIDINOALKYLHVIIDES Kurt J. Rorig, Glenview, Ill., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Dec. 28, 1959, Ser. No. 862,086 8 Claims. (Cl. 260-287) This invention relates to benzopiperidinoalkylimides and processes for the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula wherein R represents hydrogen or an alkoxy radical, and Z represents a radical of the formula N R l l and tetrahydroisoquinolines are contemplated herein, these congeneric substances alike being adapted to the purposes of the invention set forth.

Among the alkoxy radicals represented by R in the foregoing formulas, especially lower alkoxy radicals are preferred, which is to say radicals of the formula lower alkyl--O- the lower alkyl constituent being such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, penty'l, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and homologous C H groupings wherein n is a positive integer amounting to less than 9.

The alkylene radicals represented by Alk in the formulas also are desirably of'lower order, for example, methylene,'ethyl'ene, trimethylene, propylene, tetramethylene, 2,2-dimethyl-1,3-propylene, and homologous bivalent saturated acyclic straightor branched-chain hydrocarbon groupings of empirical formula wherein n is a small positive integer.

As to the imido radicals represented by Im in the formulas, these are optimally cyclic imido radicals wherein T represents an alkylene, alkenylene, or orthodivalent monoc-arbocyclic radical consisting of 6 annular ice carbon atoms to which more than 3 and fewer than 11 hydrogen atoms are attached. Illustrative of such radicals but not limiting thereto are succinimido, glutarimido, flethyl-B-methylglutarimido, maleimido, cyclohex-ane-1,2- dicarboxirnido, 1 cycloheXene-4,S-dicarboximido, 2,6- cyclohexadiene-1,2dicarb0ximido, phthalimido, etc.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. Not only are they capable of inhibiting the hyperemia and swelling characteristic of the inflammatory response to tissue injury but, additionally, they are CNS(central nervous system)-aifectant and anti-fungal agents.

Manufacture of the imidomethyl compounds of this invention proceeds by heating an appropriate tetrahydroquinoline or tetrahydroisoquinoline of the formula wherein R is defined as above and Z represents a methylenearnine radical --CH NH- with formalin and a selected imide of the formula ImI-I Im being defined as above and H being attached to nitrogen as in H N o: =o T Im being defined as before, Alk' standing for lower alkylene exclusive of methylene and attached to nitrogen, and Hal representing chlorine or bromine, and a base such as trimethylamine, potassium carbonate, or sodium hydroxide for the imide, formalin, and alcohol called for in the aforesaid manufacture of imidomethyl products; A ketonic solvent such as butanone is employed if the base is a solid.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced with-out departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 1,2,3,4-tetrahydro-2-succinimidomethylisoquinoline e To asolution of 11 parts of succinimide in parts of absolute ethanol is added 30 parts of 36% formalin l,2,3,4-tetrahydro-1-phthalimidomethylquinoline as paleand 13 parts of 1,2,3,4-tetrahydroisoquinoline. The reyellow flakes melting at 120-121.5. The product has the sultant mixture is heated at approximately 90 for 2 formula hours. Upon cooling to a crystalline precipitate is thrown down. Filtered off and dried in air, the precipi- 5 ll tate, which is in the form of white needles, melts at 121- 123. The product thus isolated is 1,2,3,4-tetrahydra-2- I succinimidomethylisoquinoline. It has the formula 0 N-GH N EXAMPLE 5 O 1 ,2,3,4-tetrahydr0-6 -meih0xy-1 -phthalimid0methyl- EXAMPLE 2 quinoline To a solution of 5 parts of phthalimide in '50 parts of absolute ethanol is added 10 parts of 36% formalin and 5 parts of l,2,3,4-tetrahydro-6-methoxy-quinoline. The resultant mixture is heated at approximately 90 for hour, then cooled to 0". Precipitation occurs. The pre- (A) N-(5-br omopentyl)succinimide.--To a solution of parts of succinirnide in 160 parts of absolute ethanol is added a solution of 5 parts of sodium in 110 parts of absolute ethanol. Solvent is removed by vacuum distillat l l d d 22 253233 fi j if ggi ggagig gis fi f 20 ciprtate, filtered oif and dried m an, consists of orange l35-145 under reflux overnight, then cooled to room fl f needles i temperature and filtered. The filtrate is distilled in vacuo mfldoinethylqmnohne meltmg approxlmately 1505- to remove excess dibromopentane. The residue, a viscous 1315 The Product has the fol mula oil, is extracted with a mixture of heptanes boiling in the 25 0 range 77-115 Solvent is stripped from the extract by distillation, leaving as a residue the desired N-(S-bromopentyl succinimide.

N (B) 1,2,3,4-tetrahydr0-2-(5-succinimidopentyl)-isoquin- I Q oline.A mixture of 13 parts of l,2,3,4-tetrahydroisoquinoline, '25 parts of N-(5-brornopentyl)succinimide, 14 E300 V parts of anhydrous powdered potassium carbonate, and

100 parts of butanone is heated at the boiling point of the EXAMPLE .6

solvent under reflux with agitation for 24 hours. Insoluh 2 3 44 I d hth th ble matter is then removed by filtration, following which 8 er Oxy elaly m p mm! mm y solvent is evaporated at 90-400 C., leaving a brown oil. qumolme The oil is taken up in dilute hydrochloric acid, and the 11btlmt10fl 0f Parts Of gj y- Y acid solution is then washed with ether to remove neutral qulnollllfi [P p as descflbed 111 B611, 2571] for material. Alkalization with aqueous 25% sodium hy- 5 P 0f 2. a y Yq droxide aifords a mixture which is extracted with ether. 40 callefi for 111 a p 5 afiofds, Y' .P 9 1 Upon evaporation of solvent from the ether extract, the detalled, y-h fi, y -p desired 1,2,3,4-tetrahydro 2 (5-succinimidopentyl)-isoylq l 0f t formula quinoline is obtained as the residue. The product has the 0 formula H5020 CH2N O l l V N N0H,oH,0H=cHcHq-N 0 l u EXAMPLE 3 What 18 clalmed is:

l. A compound of the formula 1,2,3,4-tetrahydro-2-phthalimid0methylisoquin'oline To .a solution of 16 parts of phthalimide and 140 parts of absolute ethanol is added 30 parts of 36% formalin and 13 parts of 1,2,3,4-tetrahydroisoquinoline. The resultant mixture is heated at approximately 90 for 2 hours. Upon cooling to 0, an ivory-colored crystalline precipiwherein R represents a member of the class consisting of tate is thrown down. Separated by filtration and dried hydrogen and lower alkoxy radicals, and Z represents a in air, the precipitated material is found to melt at 130- radical of the formula 132. This material is 1,2,3,4-tetrahydro-2-phthalimidomethylisoquinoline, of the formula l CH N-AlkX in which Alk represents a loweralkylene radical and X v represents a member of the class consisting of succinirnido and phthalimido radicals.

2. A compound of the formula l EXAMPLE 4 AlkN 1,2,3,4-tetrahydr0-1-phthalimidomethylquinoline o Substitution of 13 parts of 1,2,3,4-tetrahydroquinoline for the 13 parts of l,2,3,4-tetrahydroisoquinoline called .wherein Alk represents a lower alkylene radical. for in Example 3 affords, by the procedure .there detailed, 3. l,2,3,4-tetrahydro-2:succinirnidomethylisoquinoline.

6 4. A compound of the formula 6. 1,2,3,4-tetrahydro-1-phtha1imidomethy1quinoline.

7. A compound of the formula O 1 V 5 cHr-N wherein Z represents a radical of the formula O 0 lower alkoxy I --CH2NCH2-N o 8. 1,2,3,4-tetrahydro-6-methoxy 1 phthalimidomethyl- 0 quinoline.

5. 1,2,3,4-tetrahydru-2-phthalimidomethylisoquinoline. No references cited. 

1. A COMPOUND OF THE FORMULA 